WO1992021340A1 - Methode de traitement de l'encephalite infectieuse d'origine virale, bacterienne ou parasitaire - Google Patents

Methode de traitement de l'encephalite infectieuse d'origine virale, bacterienne ou parasitaire Download PDF

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Publication number
WO1992021340A1
WO1992021340A1 PCT/US1992/004454 US9204454W WO9221340A1 WO 1992021340 A1 WO1992021340 A1 WO 1992021340A1 US 9204454 W US9204454 W US 9204454W WO 9221340 A1 WO9221340 A1 WO 9221340A1
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WO
WIPO (PCT)
Prior art keywords
encephalitis
accordance
vims
pathogen
mycoplasma
Prior art date
Application number
PCT/US1992/004454
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English (en)
Inventor
Edward W. Bernton
Frank C. Tortella
Original Assignee
United States Of America, As Represented By The Secretary Of The Army
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by United States Of America, As Represented By The Secretary Of The Army filed Critical United States Of America, As Represented By The Secretary Of The Army
Publication of WO1992021340A1 publication Critical patent/WO1992021340A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to the use of effective therapeutic agent(s)
  • NMDA n-methyl aspartic acid
  • various receptor subtypes are defined by their preferential binding and excitation by quisqualate, kainic acid, and glutamic
  • encephalitides are minimal, and discordant with the degree of CNS dysfunction or physiologic impairment. This statement also applies to the encephalopathic changes which frequently complicate Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • Mycoplasma infection by the M. fermentens strain may play a role as a co-pathogen in AIDS, as suggested by Lo and Montagnier, and M. fermentens has been identified in brain, as well as liver, spleen and kidney
  • TNF tumor necrosis factoralpha
  • TNF release is a frequent tissue response to viral, parasitic, or bacterial infections, and brain tissue contains abundant microglia, immune accessory cells which can produce TNF. This data therefore suggests that TNF production leads to excitatory amino acid mobilization and that these events mediate a final common mechanism of neuronal damage following infectious and immunologic stimuli.
  • drugs which protect neurons from amino acid excitoxicity when this system is triggered in vitro by mycoplasma or endotoxin should likewise protect neurons and preserve central nervous system function in diverse infections resulting in encephalitis (brain infection or inflammation) and/or in encephalopathy (brain disfunction).
  • the patient with antagonist drugs specifically blocking the functioning of the neuronal excitatory amino acid receptor the main type of which is known as the N-methyl aspartate-binding receptor, or of treatment of the patients with other drugs which block amino acid excitotoxicity by inhibiting release of endogenous excitatory amino acids.
  • Figure 1 shows electron photomicrographs of neurons from rat fetal brain cultures exposed to culture fluids from monocytes either: A. uninfected with mycoplasma
  • FIG. 2 shows neuronal cell cultures at 20 days were exposed to 1000 colony forming units/ml mycoplasma. Cultures were photographed before mycoplasma infection and at daily intervals thereafter. AT 72 hours,
  • Figure 3 shows 100 x magnification photomicrogrphas of cresyl-violet stained neuronal cultures 3 days following addition of A. inactive vehicle, B. 1/0000 dilution of mycoplasma fermentans, C. protective 2.5 microMolar addition of MK-801, D. non-protective 0.5 micromolar addition of MD-801, E. protective 20 micromolar addition of 7-chlorokyurenic acid, F. protective 20 micromolar addition of 20 micromolar DTG, G. protective 20 micromolar addition of carbetopentane.
  • Figure 4 shows 100 x magnification phase-contrast photomicrog ⁇ has of living neuronal cultures 48 hours following addition of A and B. nothing, C. bacterial endotoxin, 500 ng./ml., D. bacterial endotoxin and 5 micromolar each dextrometho ⁇ han and MK-801, E. 1000 units/ml or recombinant mouse tumor necrosis factor alpha (TNG), F. 1000 units/ml of
  • TNF TNF
  • H 300 units/ml of TNF and 5 micromolar each dextrometho ⁇ han and MK-801.
  • excitatory amino acids may possibly also be present in excessive concentrations, such as quinolinic acid, which accumulates due to the increased activity of indoleamine 2,3 -dioxygenase induced by immune cytokines such as gamma-interferon. Ischemia due to microvascular compromise, as in cerebral malaria, also would increase concentrations of glutamic acid in the neuronal
  • this invention in its preferred embodiment, consists of the use of MK-801, or any other potent NMDA-receptor antagonist, for the treatment of acute infectious encephalitis, at an effective dose to prevent excitotoxic damage to neurons. This would improve the physiologic and clinical manifestations of the infectious disease, minimizing both permanent CNS damage and death as clinical outcomes.
  • encephalopathy in patients with severe bacterial infection or sepsis in whom cerebrospinal fluid concentrations of the excitatory amino acid quinolinic acid are increased due to activation of the immune system, may be treated with MK-801, of any other potent NMDA-receptor antagonist to
  • this invention relates to a method for the treatment of a mammal (human or nonhuman) suffering from encephalitis or encephalopathy caused by a pathogen comprising administering to said mammal a therapeutically-effective amount of a pharmaceutical composition comprising MK-801, dextrometho ⁇ han, carbetopentane, 7-chlorokyurenic
  • the encephalopathy or encephalitis can be infectious or parainfectious.
  • the pathogens which are the causative agents of the encephalitis or encephalopathy are selected from the group consisting essentially of a virus, bacterium and parasite, or a combination thereof.
  • An illustrative group of viral pathogens include arboviruses, Japanese B, St.
  • the causative pathogenic agent or pathogen can be a combination of a vims and bacterium, such as a HTV-1 vims .and Mycoplasma fermentans. It is also contemplated that the encephalitis associated with acute severe bacterial infection can be acute meningio-encephalitis.
  • compositions of matter useful, in accordance with this invention, for the treatment of a mammal (human or nonhuman) suffering from encephalitis or encephalopathy caused by a pathogen comprise a therapeutically-effective amount of an active ingredient selected from the group consisting essentially of MK-801, dextrometho ⁇ han, carbetopentane, 7-chlorokyurenic acid, caramiphen, a neuronprotective kappa opioid agonist such as CI-972, dithiolguanidine (DTG), excitatory aminoacid-induced or NMDA-induced neuronal excitotoxicity antagonists, or mixtures thereof.
  • active ingredients are MK-801, dextrometho ⁇ han, caramiphen, and carbetopentane.
  • EXAMPLE 1 Pure culture of Mycoplasma fermentans, strain incognitus, titer approximately 10 8 per ml were obtained from Dr. S.C. Lo and added at dilution of 1/1000, 1/10000, and 1/100,000 to 22 day old cultures of fetal rat neurons. Control wells received sham innocula. Other wells were identically innoculated 30 minutes after pre-treatment by addition of 10 microM MK-8-1.
  • M. fermentans caused a dose-dependent and selective initial
  • mycoplasma showed many viable neurons comparable to the pre-innoculation population. Wells with mycoplasma and vehicle all showed lysis or loss of approximately 80% of the neuronal population. All of the above dmgs were completely neuroprotective at 20 micromolar and many were protective at 2 micromolar. EXAMPLE 3 Subsequently additional experiments were conducted to examine the mechanism of mycoplasma-induced neuronotoxicity. It was found that killed mycoplasma which are non-infective were able to cause neuronal death. This suggests the killing of neurons was mediated by a host response to the
  • Bacterial endotoxin which potently evokes host immune responses involving the secretion of Interleukin-1, Interleukin-6, and Tumor-necrosis factor, which have been
  • Bacterial endotoxin was also neuronotoxic, at concentrations of 25 ng/ml and above, and most importantly, this toxicity was
  • mammalian cytokines induced by LPS were screened for neuronotoxicity, including gamma-interferon, IL-2, IL-1, IL-6, TGF-beta, M-CSF, and TNF alpha. Only addition of TNF alpha to cultures was found to cause neuronal destruction similar to that seen following addition of LPS or Mycoplasma.
  • EXAMPLE 4 A thirty year old soldier stationed in Germany is admitted to the hospital with fever, stiff neck, and mild delirium. He was hiking in the woods
  • EXAMPLE 5 A first grade student is brought to a hospital emergency room during a summer outbreak of sporadic St. Louis Equine encephalitis, following onset of fever and a seizure. Spinal tap and EEG are consistent with viral encephalitis, he becomes stuporous on his second hospital day. Treatment is instituted with dextrometho ⁇ han, (effective adult dose 100 to 200 mg every 6 hours orally) at half the adult dose, via a nasogastric tube.
  • EXAMPLE 6 Following a viral illness which was treated by the mother with aspirin, an 8 year old girl develops nausea, vomitting, and confused behavior.
  • EXAMPLE 7 A 67 year old male was alcoholic cirrohsis, portal hypertension, and ascites becomes slightly febrile and quite disoriented. A tap of his abdominal ascites shows bacteria and white cells, and the diagnosis of spontaneous bacterial peritonitis with encephalipathy due to liver disease and
  • An in vitro neuronal culture model for adenovirus-induced neuronotoxicity is being developed as a secondary in vitro dmg screen, and we are developing an arbovims screen which could be used at research facilities with level III biologic containment.

Abstract

Compositions pharmaceutiques et méthode d'utilisation de ces compositions pour le traitement pharmacologique de l'encéphalite et de l'encéphalopathie infectieuses et para-infectieuses d'origines diverses, permettant d'éviter ou de minimiser les dommages neuronaux et les troubles du système nerveux central.
PCT/US1992/004454 1991-06-05 1992-05-27 Methode de traitement de l'encephalite infectieuse d'origine virale, bacterienne ou parasitaire WO1992021340A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US71060291A 1991-06-05 1991-06-05
US710,602 1991-06-05

Publications (1)

Publication Number Publication Date
WO1992021340A1 true WO1992021340A1 (fr) 1992-12-10

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AU (1) AU2159792A (fr)
WO (1) WO1992021340A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0914115A1 (fr) * 1996-04-10 1999-05-12 Walter E. Kozachuk Methodes de neuroprotection
US7652025B2 (en) * 2001-05-08 2010-01-26 Toray Industries, Inc. Remedies for sepsis

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4888347A (en) * 1986-01-14 1989-12-19 Merck Sharp & Dohme Limited Use of specific N-methyl-D-aspartate receptor antagonists in the prevention and treatment of neurodegeneration
USH734H (en) * 1988-03-07 1990-02-06 E. R. Squibb & Sons, Inc. Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor
US5034400A (en) * 1989-10-20 1991-07-23 Olney John W Method for preventing neurotoxic side effects of NMDA antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4888347A (en) * 1986-01-14 1989-12-19 Merck Sharp & Dohme Limited Use of specific N-methyl-D-aspartate receptor antagonists in the prevention and treatment of neurodegeneration
USH734H (en) * 1988-03-07 1990-02-06 E. R. Squibb & Sons, Inc. Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor
US5034400A (en) * 1989-10-20 1991-07-23 Olney John W Method for preventing neurotoxic side effects of NMDA antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 114, No. 19, issued 28 October 1991, (Columbus, Ohio, USA), TSIANG et al., "Inhibition of rabies virus infection in cultured rat cortial neurons by an N-methyl-d-aspartate noncompetitive antagonist, MK-801", (Rabies unit, Pasteur Institute 75724 Paris Fr.); ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 1991, 35(3), 572-74, the Abstract No. 199133W. *
CHEMICAL ABSTRACTS, Volume 115, No. 3, issued 22 July 1991, (Columbus, Ohio, USA), OLNEY, "Use of combined excitatory amino acid and cholinergic antagonists to prevent neurological deterioration", Abstract No. 248123Z; & US,A,5 034 400, (23-07-91). *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0914115A1 (fr) * 1996-04-10 1999-05-12 Walter E. Kozachuk Methodes de neuroprotection
EP0914115A4 (fr) * 1996-04-10 2002-07-31 Walter E Kozachuk Methodes de neuroprotection
US7652025B2 (en) * 2001-05-08 2010-01-26 Toray Industries, Inc. Remedies for sepsis

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AU2159792A (en) 1993-01-08

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